Bombesin antagonists with deletion of net-residue at the c-terminus

Abstract

The invention relates to a polypeptide of formula I: R.sup.1 -A.sup.1 -A.sup.2 -A.sup.3 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A 7 -A 9 -Q wherein each of the generic terms is disclosed in full in the specification and includes: R 1 is (2-6C)alkanoyl or (1-4C)alkoxycarbonyl; A 1 is a direct link to A 2 , or is Gly or Arg; A 2 is a direct link to A 3 , or is Gly or Pro; A 3 is a direct link to A 4 , or is Lys or Lys(Z); A 4 is His or D-His; A 5 is Trp or MeTrp; A 6 is Ala or MeAla; A 7 is Val or MeVal; A 8 is Gly or Sar; A 9 is His or MeHis; and Q is a group of the formula -A 10 .R 2 in which A 10 is Leu or D-Leu and R 2 is hydroxy, amino, (1-3C)alkylamino or (1-3C)alkoxy; or Q is (1-6C)alkoxy or (1-10C)alkylamino; provided that when R 1 is acetyl and -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -Q is -His-Trp-Ala-Val-Gly-His-Leu-NH 2 then -A 1 -A 2 -A 3 - is not a direct link to His. The compounds possess antagonist properties against bombesin-like peptides and are of value in the treatment of malignant disease in warm-blooded animals.

What is claimed includes the following: 
     
       1. A polypeptide of formula I:   R.sup.1 -A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -Q                                      I     wherein   R 1  is hydrogen or (1-6C)alkyl which may optionally bear a phenyl substituent, and wherein said phenyl substituent may optionally bear a substituent selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, cyano and nitro, or R 1  is (2-6C)alkanoyl which may optionally bear one or more substituents selected from carboxy, (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di[(1-4C)alkyl]amino, phenyl, phenoxy, naphthyl, imidazolyl, napthyloxy, pyridyl, indolyl and thienyl, and wherein any one or more of said aryl, phenoxy, naphthyloxy or heteroaryl groups may optionally bear one or more substituents selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy, cyano and nitro; or   R 1  is (4-6C)cycloalkoxycarbonyl; or R 1  is (1-4C)alkoxycarbonyl which may optionally bear one or two phenyl substituents and wherein either one or both of said phenyl substituents may optionally bear a halogeno, nitro or (1-4C)alkoxy substituent;   wherein A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, L-Nal, D-Nal, D-pcF, D-pfF, D-dcF, Pro, D-Deh, βAla or Glp;   wherein A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   wherein A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   wherein A 4  is His, D-His, MeHis, EtHis, PrHis, His(τ-Me), His(π-Me), D-Gln, D-Glu(OMe), D-Glp, Leu, D-Leu, MeLeu, Lys, Pal, D-Pal, Phe, D-Phe, Pro, Arg, Glu, His(COPh), Trp or Thr;   wherein A 5  is Trp, MeTrp, Trp(Me), Trp(For), Val, DL-Flg, L-Nal, pcF, Leu, Lys, Pal, Cha, Lys(Z(2Cl)) or Lys(COCH 3 );   wherein A 6  is Ala, MeAla, Aib, Gly, Pro, Leu, Phe, D-Phe, Ser, Val, L-Nal, Thr, Arg or Glu;   wherein A 7  is Val, MeVal, Aib, Leu, Ile, Thr(CH 2  Ph), Thr, Phe, D-Phe, Lys(Z(2Cl)), Ser or DL-Flg;   wherein A 8  is Gly, Sar, Ala, D-Ala, D-Ser, D-Ser(CH 2  Ph), D-pcF, D-Ala(NH 2 ), D-Ala(NHZ(Cl)), Aib, D-Pro, D-Lys, Asp, D-Arg, D-Lys(Z(2Cl)), Val, Ac 3  c, Ac 5  c or Ac 6  c;   wherein A 9  is His, MeHis, His(τ-Me), His(π-Me), D-pcF, Aib, Val, Leu, MeLeu, Ala, Ile, Ahx, Ape, Met, Pro, Phe, D-Phe, Gln, Lys, Lys(Z), Pal, Ser, Ser(CH 2  Ph), Thr, Thr(CH 2  Ph), Glu, Asp, Asp(OBu t ), Trp or L-Nal; and   wherein Q is a group of the formula -A 10 .R 2  in which A 10  is Leu, D-Leu, MeLeu, Ile, MeIle, Ahx, MeAhx, Aib, Pro, Val, MeVal, Phe, Ape, MeApe, Met, Ser, Gln, Glu or Trp and R 2  is hydroxy or amino; or R 2  is (1-3C)alkylamino, dialkylamino of up to 4 carbon atoms, or (1-3C)alkoxy, each optionally bearing a hydroxy, (1-3C)alkoxy, amino, (1-6C)alkylamino, dialkylamino of up to 8 carbon atoms, or phenyl-(1-3C)alkylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a fluoro-(1-3C)alkyl or phenyl substituent; or   R 2  is (3-6C)cycloalkylamino, N-alkyl-N-cycloalkylamino of up to 8 carbon atoms, or dicycloalkylamino of up to 12 carbon atoms; or R 2  is 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl or 4-methylpiperazin-1-yl; or   Q is (1-6C)alkoxy, (1-10C)alkylamino or dialkylamino of up to 10 carbon atoms each optionally bearing a hydroxy, amino, (1-3C)alkoxy, (1-6C)alkylamino, dialkylamino of up to 8 carbon atoms, phenyl-(1-3C)alkylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a phenyl substituent; or Q is phenyl-(1-3C)alkylamino; or   Q is (3-6C)cycloalkylamino, N-alkyl-N-cycloalkylamino of up to 8 carbon atoms or dicycloalkylamino of up to 12 carbon atoms; or Q is 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl or 1-homopiperidinyl each optionally bearing on any available position, including on any available nitrogen atom, a substituent selected from (1-6C)alkyl, phenyl and phenyl-(1-3C)alkyl; and wherein within R 2  or Q a phenyl group may optionally bear a substituent selected from halogeno, (1-4C)alkyl, (1-4C)alkoxy, hydroxy and cyano;   or a pharmaceutically-acceptable salt of said polypeptide; provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       2. A polypeptide of formula I   R.sup.1 -A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -Q                                      I     wherein   R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, benzyloxycarbonyl, phenylacetyl, 3-phenylpropionyl, 4-chlorophenylacetyl, 3-chlorophenylacetyl, 4-bromophenylacetyl, 4-fluorophenylacetyl, naphthylacetyl, imidazolylacetyl, pyridylacetyl, thienylacetyl, indolylacetyl, phenoxyacetyl, naphthyloxyacetyl, 3-carboxypropionyl, 3-methoxycarbonylpropionyl, glycyl, 3-aminopropionyl, tert-butoxycarbonyl or cyclopentyloxycarbonyl; wherein A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, D-pcF, D-Deh, L-Nal, βAla, D-Nal or Pro;   wherein A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   wherein A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or DpcF;   wherein A 4  is His, D-His, MeHis, EtHis, PrHis, His(τ-Me), His(π-Me), D-Gln, Lys, Pal, D-Pal, Phe, Pro, D-Glu(OMe), D-Glp or Trp;   wherein A 5  is Trp, MeTrp, Trp(Me), Trp(For), L-Nal, pcF, Lys or Pal;   wherein A 6  is Ala, MeAla, Aib, Gly, Leu, Ser, Val or Thr;   wherein A 7  is Val, MeVal, Aib, Leu, Ile or Thr;   wherein A 8  is Gly, Sar, D-Ala, D-Ser, D-Ser(CH 2  Ph), D-pcF, Aib or D-Pro;   wherein A 9  is His, MeHis, His(τ-Me), His(π-Me), Val, Leu, Pro, Phe, Gln, Lys, Lys(Z) or Pal; and   wherein Q is a group of the formula -A 10 .R 2  in which A 10  is Leu, D-Leu, MeLeu, Ile, Ahx, Aib, Val, Phe, Ape or Met and R 2  is hydroxy or amino; or R 2  is (1-3C)alkylamino, dialkylamino of up to 4 carbon atoms or (1-3C)alkoxy, each optionally bearing an amino, (1-6C)alkylamino or phenyl-(1-3C)alkylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a fluoro-(1-3C)alkyl or phenyl substituent; or R 2  is (3-6C)cycloalkylamino; or R 2  is 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl;   or Q is methoxy, isopropoxy, isobutoxy, isopentyloxy, methylamino, isobutylamino, isopentylamino, 1-ethylpropylamino or 1,3-dimethylbutylamino, each optionally bearing an amino, methylamino, isopropylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a phenyl substituent, or Q is benzylamino or phenethylamino;   or Q is (3-6C)cycloalkylamino;   or Q is 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl, each optionally bearing on any available position, including on any available nitrogen atom, a substituent selected from (1-6C)alkyl, phenyl and phenyl-(1-3C)alkyl; and wherein within Q a phenyl group may optionally bear a substituent selected from chloro, methyl, methoxy and hydroxy; or a pharmaceutically-acceptable salt thereof; provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       3. A polypeptide of the formula I as claimed in claim 2 wherein   R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, acetyl, propionyl, isobutyryl, isovaleryl, benzyloxycarbonyl, phenylacetyl, 3-phenylpropionyl, 4-chlorophenylacetyl, naphth-2-ylacetyl, 4-pyridylacetyl, indol-3-ylacetyl, naphth-2-yloxyacetyl, 3-carboxypropionyl or tert-butoxycarbonyl;   A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, D-pcF, D-Deh, L-Nal, βAla, D-Nal or Pro;   A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   A 4  is His, D-His, His(τ-Me), His(π-Me), D-Gln, Leu, Lys, Pal, D-Pal, Phe, Pro, D-Glu(OMe) or D-Glp; A 5  is Trp or MeTrp; A 6  is Ala, MeAla or Aib; A 7  is Val; A 8  is Gly, Sar, D-Ala, D-Ser, D-Ser(CH 2  Ph), D-pcF, Aib or D-Pro; A 9  is His, MeHis, His(τ-Me), His(π-Me), Leu, Pro, Gln, Phe, Lys, Lys(Z) or Pal; and   Q is a group of the formula -A 10 .R 2  in which A 10  is Leu, MeLeu, Phe or Val and R 2  is methoxy, amino or methylamino, each optionally bearing a trifluoromethyl or phenyl substituent, or R 2  is ethoxy or ethylamino, each optionally bearing an amino, methylamino, ethylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a trifluoromethyl or phenyl substituent;   or R 2  is cyclopentylamino or 1-pyrrolidinyl;   or Q is methoxy, isopropoxy, isobutoxy, isopentyloxy, methylamino, isobutylamino, isopentylamino, 1-ethylpropylamino or 1,3-dimethylbutylamino, each optionally bearing an amino, methylamino, isopropylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a phenyl substituent, or Q is benzylamino or phenethylamino;   or Q is cyclopentylamino, cyclohexylamino, piperidino, 4-phenylpiperidino, morpholino or 4-benzylpiperazin-1-yl;   or a pharmaceutically-acceptable acid-addition salt thereof;   provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       4. A polypeptide of formula I   R.sup.1 -A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -Q                                      I     wherein   R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, acetyl, propionyl, butyryl, benzyloxycarbonyl, phenylacetyl, 3-phenylpropionyl, 4-chlorophenylacetyl, 3-chlorophenylacetyl, 4-bromophenylacetyl, 4-fluorophenylacetyl, naphthylacetyl, imidazolylacetyl, pyridylacetyl, thienylacetyl, indolylacetyl, phenoxyacetyl, naphthyloxyacetyl, 3-carboxypropionyl, 3-methoxycarbonylpropionyl, glycyl, 3-aminopropionyl, tert-butoxycarbonyl or cyclopentyloxycarbonyl;   wherein A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, D-pcF, D-Deh, L-Nal, βAla, D-Nal or Pro;   wherein A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   wherein A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   wherein A 4  is His, D-Gln, Lys, Pal, D-Glu(OMe) or D-Glp;   wherein A 5  is Trp, MeTrp, Trp(Me), Trp(For), L-Nal, pcF, Lys or Pal;   wherein A 6  is Ala, MeAla, Aib, Gly, Leu, Ser, Val or Thr;   wherein A 7  is Val, MeVal, Aib, Leu, Ile or Thr;   wherein A 8  is Gly, Sar, Ala, D-Ala, D-Ser, Aib, D-Pro or Phe;   wherein A 9  is His, MeHis, His(τ-Me), His(π-Me), Gln or Lys; and   wherein Q is a group of the formula -A 10 .R 2  in which A 10  is Leu, D-Leu, MeLeu, Ile, Ahx, Aib, Val, Ape or Met and R 2  is hydroxy or amino; or R 2  is (1-3C)alkylamino, dialkylamino of up to 4 carbon atoms or (1-3C)alkoxy, each optionally bearing an amino, (1-6C)alkylamino or phenyl-(1-3C)alkylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a fluoro-(1-3C)alkyl or phenyl substituent; or R 2  is (3-6C)cycloalkylamino; or R 2  is 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl;   or Q is methoxy, isopropoxy, isobutoxy, isopentyloxy, methylamino, isobutylamino, isopentylamino, 1-ethylpropylamino or 1,3-dimethylbutylamino, each optionally bearing an amino, methylamino, isopropylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a phenyl substituent, or Q is benzylamino or phenethylamino;   or Q is (3-6C)cycloalkylamino;   or Q is 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl, each optionally bearing on any available position, including on any available nitrogen atom, a substituent selected from (1-6C)alkyl, phenyl and phenyl-(1-3C)alkyl; and   wherein within Q a phenyl group may optionally bear a substituent selected from chloro, methyl, methoxy and hydroxy; or a pharmaceutically-acceptable salt thereof;   provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       5. A polypeptide of the formula I as claimed in claim 4 wherein   R 1  is hydrogen, methyl, ethyl, propyl, isopropyl, acetyl, propionyl, benzyloxycarbonyl, phenylacetyl, 3-phenylpropionyl, 4-chlorophenylacetyl, naphth-2-ylacetyl, indol-3-ylacetyl, naphth-2-yloxyacetyl, 3-carboxypropionyl or tert-butoxycarbonyl;   A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, D-pcF, D-Deh, L-Nal, βAla, D-Nal or Pro;   A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   A 4  is His, D-Gln, Lys, Pal, D-Glu(OMe) or D-Glp; A 5  is Trp or MeTrp;   A 6  is Ala, MeAla or Aib; A 7  is Val; A 8  is Gly, Sar, D-Ala, Aib or D-Pro; A 9  is His, MeHis, His(τ-Me), His(π-Me), Gln or Lys; and   Q is a group of the formula -A 10 .R 2  in which A 10  is Leu or Val and R 2  is methoxy, amino or methylamino, each optionally bearing a trifluoromethy or phenyl substituent, or   R 2  is ethoxy or ethylamino, each optionally bearing an amino, methylamino, ethylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a trifluoromethyl or phenyl substituent;   or R 2  is cyclopentylamino or 1-pyrrolidinyl;   or Q is methoxy, isopropoxy, isobutoxy, isopentyloxy, methylamino, isobutylamino, isopentylamino, 1-ethylpropylamino or 1,3-dimethylbutylamino, each optionally bearing an amino, methylamino, isopropylamino, isobutylamino, isopentylamino, benzylamino or phenethylamino substituent, other than in a position alpha to an oxygen or nitrogen atom, or a phenyl substituent, or Q is benzylamino or phenethylamino;   or Q is cyclopentylamino, cylcohexylamino, piperidino, 4-phenylpiperidino, morpholino or 4-benzylpiperazin-1-yl;   or a pharmaceutically-acceptable acid-addition salt thereof; provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       6. A polypeptide of the formula I as claimed in claim 4 wherein   R 1  is hydrogen, isopropyl, acetyl, propionyl, benzyloxycarbonyl, 3-phenylpropionyl, 4-chlorophenylacetyl, naphth-2-ylacetyl, indol-3-ylacetyl, naphth-2-yloxyacetyl, 3-carboxypropionyl or tert-butoxycarbonyl;   A 1  is a direct link to A 2 , or is Gly, Arg, D-Arg, Lys, Lys(Z), Phe, D-Phe, Asp, D-pcF, D-Deh, L-Nal, βAla, D-Nal or Pro;   A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   A 4  is His, D-Gln or D-Glu(OMe);   A 5  is Trp; A 6  is Ala; A 7  is Val;   A 8  is Gly, Sar or D-Ala; A 9  is His; and   Q is a group of the formula -A 10 .R 2  in which A 10  is Leu and R 2  is methoxy, amino, methylamino, ethylamino or dimethylamino;   or Q is methoxy or isopentylamino;   or a pharmaceutically-acceptable salt thereof; provided that when -A 4  -A 5  -A 6  -A 7  -A 8  -A 9  -A 10  - is -His-Trp-Ala-Val-Gly-His-Leu-, and -A 1  -A 2  -A 3  - is a direct link, then R 1  is not hydrogen or acetyl.   
     
     
       7. A polypeptide of formula I   R.sup.1 -A.sup.1 -A.sup.2 -A.sup.3 -A.sup.4 -A.sup.5 -A.sup.6 -A.sup.7 -A.sup.8 -A.sup.9 -Q                                      I     wherein   R 1  is hydrogen, acetyl, propionyl, butyryl, benzyloxycarbonyl, 3-phenylpropionyl, naphthylacetyl, tert-butoxycarbonyl or cyclopentyloxycarbonyl;   wherein A 1  is Gly, Arg, Lys(Z), Phe, D-Phe, D-pcF, D-Deh, L-Nal, D-Nal or Pro;   wherein A 2  is a direct link to A 3 , or is Gly, Pro or Asn;   wherein A 3  is a direct link to A 4 , or is Lys, Lys(Z), D-Nal or D-pcF;   wherein A 4  is His, D-His or D-Gln;   wherein A 5  is Trp; wherein A 6  is Ala; wherein A 7  is Val;   wherein A 8  is Gly or D-Ala; wherein A 9  is His;   and wherein Q is a group of the formula -A 10 .R 2  in which A 10  is Leu and R 2  is hydroxy, amino, (1-3C)alkylamino, dialkylamino of up to 4 carbon atoms or (1-3C)alkoxy;   or Q is (1-6C)alkoxy, (1-6C)alkylamino or dialkylamino of up to 8 carbon atoms;   or a pharmaceutically-acceptable salt thereof.   
     
     
       8. A pharmaceutical composition suitable for producing a bombesin-antagonist effect in a warm-blooded animal in need of such treatment which comprises an effective amount of a polypeptide of formula I as claimed in claim 1, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
       9. A method for producing a bombesin-antagonist effect in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a polypeptide of formula I as claimed in claim 1 or a pharmaceutically-acceptable salt thereof.